Approximately 90% of new human immunodeficiency virus (HIV) infections are acquired through sexual contact. The development of safe, effective, and affordable topical microbicides for vaginal or rectal use could play a critical role in reducing HIV transmission rates worldwide. Clinical, epidemiological and molecular studies strongly support the role of herpes simplex virus (HSV) as a major cofactor for the transmission of HIV. Genital ulcers lead to breaks in the epithelial barrier and HSV induces the expression of pro-inflammatory cytokines that are known to enhance HIV replication. The goal of the proposed studies is to characterize the effects of sodium dimandelic acid ether (SAMMA) and its leading derivatives on HIV and HSV infection utilizing relevant biologic culture systems. SAMMA has excellent anti-mV and anti-HSV activity, while exhibiting no cytotoxicity in cell culture. While cell cultures may provide important information for the evaluation of microbicides, they may not adequately simulate events that occur in vivo. Human explant cultures (endocervical, ectocerivcal, vaginal and rectal), biologic fluids (cervicovaginal secretions and semen) and a mouse genital herpes model will be used in this Project to assess anatomic, physiologic, and immunologic factors that might impact on the activity of this novel class of compounds. Building on the in vitro cell culture data of Projects I, II and IV, the applicant will study the most active derivatives/isomers of SAMMA using biologic culture systems. In Aim 1, the most active derivatives will be evaluated for efficacy against HIV-1 infection of primary macrophages using human genital tract fluids and mucosal explant cultures. In Aim 2, mucosal explant cultures and a mouse model will be used to determine the efficacy of SAMMA to block HSV infection of epithelial cells. Inflammatory cells and cytokines will be measured to study the effects of SAMMA on the innate immune system (Aims 1,2 and 3). The interrelationship between HIV and HSV and the efficacy of SAMMA to inhibit dual infection will be studied in Aim 3. Efficacy and safety data in relevant biologic culture systems may provide compelling support for advancing SAMMA or one of its derivatives to clinical trials.